Assay for Predicting Risk of Capecitabine-Induced Toxicity in a Subject

Abstract

The invention provides an assay useful in predicting risk of capecitabine-induced toxicity in a subject. The subject may be screened for the presence of at least one polymorphism of the invention. Suitable polymorphisms are provided. The presence of one or more of the polymorphisms indicates an increased risk of developing capecitabine-induced toxicity; a negative result may indicate a decreased risk of developing capecitabine-induced toxicity.

1 . A method of screening for risk of capecitabine-induced toxicity in a subject, comprising screening the subject for the presence of at least one polymorphism selected from: rs12211900; rs8048167; rs10654492; rs35087079; rs117686094; rs117260063; rs12231444; rs1491207661; rs11643168; rs193272564; rs140744481; rs76211390; rs79272399; rs71313929; rs71379941; rs75217739; rs139788123; rs79986886; rs116448748; rs77911328; rs145225093; rs117241924; rs200676466; rs4972833; rs148123087; rs181841887; rs698607; rs115143613; rs147827021; rs199983532; rs1327306; rs4792825; rs78361592; rs6137844; rs2929329; rs35741121; rs56329496; rs117810108; rs149994224; rs11024884; rs111378975; rs2420201; rs11375020; rs75504333; rs11447080; rs74380254; rs66842063; rs180742844; rs527945 and rs73039836;
 wherein:   i. the presence of said at least one polymorphism indicates an increased risk of developing capecitabine-induced toxicity compared to a subject which does not possess said at least one polymorphism; and   ii. a negative result indicates no increased risk or a decreased risk of developing capecitabine-induced toxicity compared to a subject which possesses said at least one polymorphism.   
     
     
         2 . The method according to  claim 1 , comprising screening for the presence of at least one polymorphism selected from rs12211900; rs8048167; rs10654492; rs35087079; rs117686094; rs117260063; rs12231444; rs1491207661; rs11643168; rs193272564; rs140744481; rs76211390; rs79272399; rs71313929; rs71379941; rs75217739; rs139788123; rs79986886; rs116448748; rs77911328; rs145225093; rs117241924; rs200676466; rs4972833; rs48123087; and rs181841887. 
     
     
         3 . The method according to  claim 1 , comprising screening for the presence of at least one polymorphism selected from rs76211390 and rs79272399. 
     
     
         4 . The method according to  claim 1 , comprising screening for the presence of at least one polymorphism selected from rs76211390; rs77911328; rs145225093; and rs117241924. 
     
     
         5 . The method according to  claim 1 , comprising screening for the presence of at least one polymorphism selected from rs76211390; rs79272399; rs77911328; rs145225093; and rs117241924. 
     
     
         6 . The method according to  claim 1 , comprising screening for the presence of at least one polymorphism selected from rs75217739 and rs139788123. 
     
     
         7 . The method according to  claim 1 , comprising screening for the presence of at least one polymorphism selected from rs8048167; rs10654492; rs35087079; rs117686094; rs117260063; rs12231444; rs1491207661; and rs11643168. 
     
     
         8 . The method according to  claim 1 , comprising screening for the presence of at least one polymorphism selected from rs12211900 and rs71379941. 
     
     
         9 . The method according to  claim 1 , comprising screening for the presence of at least one polymorphism selected from rs8048167; rs10654492; rs35087079; rs117686094; rs117260063; rs12231444; rs1491207661; rs11643168; rs12211900; and rs71379941. 
     
     
         10 . The method according to  claim 1 , comprising screening for the presence of at least one polymorphism selected from rs193272564 and rs140744481. 
     
     
         11 . The method according to  claim 1 , comprising screening for the presence of at least one polymorphism selected from rs200676466; rs4972833; and rs148123087. 
     
     
         12 . The method according to  claim 1 , comprising screening for the presence of at least one polymorphism selected from rs193272564; rs140744481; rs200676466; rs4972833; and rs148123087 
     
     
         13 . The method according to  claim 1 , comprising screening for the presence rs181841887. 
     
     
         14 . The method according to  claim 1 , comprising screening for the presence of at least one polymorphism selected from rs79986886 and rs116448748. 
     
     
         15 . The method according to  claim 1 , comprising screening for the presence of at least one polymorphism selected from rs181841887; rs79986886; and rs116448748. 
     
     
         16 . The method according to  claim 1 , comprising screening for the presence of at least one polymorphism selected from rs8048167; rs10654492; rs35087079; rs117686094; rs117260063; rs12231444; rs1491207661; rs11643168; rs71313929; rs181841887; rs76211390; rs79272399; rs193272564; and rs140744481. 
     
     
         17 . The method according to  claim 1 , comprising screening for the presence of at least one polymorphism selected from rs12211900; rs71379941; rs75217739; rs139788123; rs79986886; rs116448748; rs77911328; rs145225093; rs76211390; rs117241924; rs200676466; rs4972833; and rs148123087. 
     
     
         18 . The method according to  claim 1 , comprising screening for the presence of at least one polymorphism selected from rs12211900; rs698607; rs115143613; rs147827021; rs199983532; rs1327306; rs4792825; rs78361592; rs6137844; rs2929329; rs35741121; rs56329496; rs117810108; rs149994224; rs11024884; rs111378975; rs2420201; rs11375020; rs75504333; rs11447080; rs74380254; rs66842063; rs180742844; rs527945 and rs73039836. 
     
     
         19 . The method according to  claim 1 , comprising screening for the presence of at least one polymorphism selected from rs147827021; rs149994224; and rs111378975 
     
     
         20 . The method according to  claim 1 , comprising screening for the presence of at least one polymorphism selected from rs2929329; rs35741121; rs56329496; rs117810108; rs149994224; rs11024884; and rs111378975. 
     
     
         21 . The method according to  claim 1 , comprising screening for the presence of at least one polymorphism selected from rs2420201; rs11375020; rs75504333; rs11447080; rs74380254; rs66842063; rs149994224; rs111378975; rs180742844; and rs527945. 
     
     
         22 . The method according to  claim 1 , comprising screening for the presence of at least one polymorphism selected from rs2929329; rs35741121; rs56329496; rs117810108; rs149994224; rs11024884; rs111378975, rs2420201; rs11375020; rs75504333; rs11447080; rs74380254; rs66842063; rs180742844; and rs527945. 
     
     
         23 . The method according to  claim 1 , comprising screening for the presence of at least one polymorphism selected from rs698607; rs115143613; rs147827021; rs199983532; rs1327306; rs4792825; and rs78361592. 
     
     
         24 . The method according to  claim 1 , comprising screening for the presence of at least one polymorphism selected from rs147827021 and rs6137844. 
     
     
         25 . The method according to  claim 1 , comprising screening for the presence of at least one polymorphism selected from rs698607; rs115143613; rs147827021; rs199983532; rs1327306; rs4792825; rs78361592; and rs6137844. 
     
     
         26 . The method according to  claim 1 , comprising screening for the presence of at least one polymorphism selected from rs698607; rs115143613; rs147827021; rs199983532; rs1327306; rs4792825; rs78361592; rs2929329; rs35741121; rs56329496; rs117810108; rs149994224; rs11024884; and rs111378975. 
     
     
         27 . The method according to  claim 1 , comprising screening for the presence of at least one polymorphism selected from rs12211900; rs147827021; rs6137844; rs2420201; rs11375020; rs75504333; rs11447080; rs74380254; rs66842063; rs149994224; rs111378975; rs180742844; rs527945; and rs73039836. 
     
     
         28 . The method according to  claim 1 , comprising screening for the presence of at least one polymorphism selected from rs698607; rs115143613; rs147827021; rs199983532; rs1327306; rs4792825; rs78361592; rs2929329; rs35741121; rs56329496; rs117810108; rs149994224; rs11024884; rs111378975; rs12211900; rs6137844; rs2420201; rs11375020; rs75504333; rs11447080; rs74380254; rs66842063; rs180742844; rs527945; and rs73039836. 
     
     
         29 . The method according to  claim 1 , wherein the subject is a cancer patient. 
     
     
         30 . The method according to  claim 29 , wherein the patient has a solid tumour cancer. 
     
     
         31 . The method according to  claim 30 , wherein the patient has colorectal cancer (CRC), or breast cancer, or gastrointestinal cancer. 
     
     
         32 . The method according to  claim 1 , wherein the subject is undergoing chemotherapy with 5-FU. 
     
     
         33 . The method according to  claim 32 , wherein the subject is undergoing capecitabine monotherapy. 
     
     
         34 . The method according to  claim 1 , wherein the screening is carried out on a fluid sample from a patient. 
     
     
         35 . The method according to  claim 34 , wherein the fluid sample is a saliva, blood serum or plasma sample. 
     
     
         36 . The method according to  claim 1 , wherein the screening is carried out on a solid sample from a patient. 
     
     
         37 . The method according to  claim 36 , wherein the solid sample is from a biopsy. 
     
     
         38 . The method according to  claim 1 , further comprising the step of monitoring the subject for one or more symptoms of capecitabine-induced toxicity in the event of a positive result. 
     
     
         39 . The method according to  claim 38 , wherein the one or more symptoms include mucositis/stomatitis, haematological toxicity, diarrhoea, nausea and vomiting, myelosuppression, neutropaenia, thrombocytopaenia, and/or hand-foot syndrome (HFS). 
     
     
         40 . The method according to  claim 39 , wherein the one or more symptoms include mucositis/stomatitis and/or haematological toxicity. 
     
     
         41 . The method of  claim 1 , wherein screening is carried out through logistic regression. 
     
     
         42 . The method according to  claim 41 , wherein a genetic score ΣβiNi is assigned to each individual, where βi is the beta coefficient of the ith SNP significantly associated with global toxicity in a logistic regression model, and Ni is the number of harmful alleles carried by that individual at that locus. 
     
     
         43 . The method according to  claim 1 , wherein the capecitabine-induced toxicity is early onset capecitabine-induced toxicity.